Abstract
Consumption of high-fat diet and alcohol is associated with obesity, leading to enhanced morbidity and mortality. This study was designed to examine the interaction between high-fat diet and the alcohol metabolizing enzyme alcohol dehydrogenase (ADH) on ethanol-induced cardiac depression. Mechanical and intracellular Ca2+ properties were measured in cardiomyocytes from ADH transgenic and Friend Virus-B type (FVB) mice fed a low- or high-fat diet for 16 weeks. Expression of protein kinase B (Akt) and Foxo3a, two proteins essential for cardiac survival, was evaluated by Western blot. Cardiac damage was determined by carbonyl formation. High fat but not ADH induced obesity without hyperglycemia or hypertension, prolonged time-to-90% relengthening (TR90), and depressed peak shortening (PS) and maximal velocity of shortening/relengthening (+/- dL/dt) without affecting intracellular Ca2+ properties. Ethanol suppressed PS and intracellular Ca2+ rise in low-fat-fed FVB mouse cardiomyocytes. ADH but not high-fat diet shifted the threshold of ethanol-induced inhibition of PS and +/- dL/dt to lower levels. The amplitude of ethanol-induced cardiac depression was greater in the high-fat but not the ADH group without additive effects. Ethanol down- and up-regulated Akt and Foxo3a expression, respectively, and depressed intracellular Ca2+ rise, the effects of which were exaggerated by ADH, high-fat, or both. High-fat diet, but not ADH, enhanced Foxo3a expression and carbonyl content in non-ethanol-treated mice. Ethanol challenge significantly enhanced protein carbonyl formation, with the response being augmented by ADH, high-fat, or both. Our data suggest that high-fat diet and ADH transgene may exaggerate ethanol-induced cardiac depression and protein damage in response to ethanol.
Published Version
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